Estudo da ação antipsicótica e efeitos colaterais do haloperidol nanoencapsulado em ratos

Abstract

Haloperidol is a typical neuroleptic widely used in the treatment of several psychotic disorders and it remains the most prescribed antipsychotic worldwide, due to its high potency and low cost. Despite its good therapeutic efficacy, the use of this drug is related to development of serious side effects of endocrine and cognitive nature, besides movement disturbances. Of particular importance, the motor disorders may be manifested in an irreversible and disabling form, whose pathophysiology has been linked to free radical generation, oxidative stress and dopaminergic neuronal death in extrapyramidal regions. Currently, polymeric nanoparticles are important terapeutic tools in the pharmaceutical area, because they permit a vectorization and a control drug release, it increasing the therapeutic efficacy and reducing adverse side effects. In this context, the present study aimed to perform a comparative evaluation among formulations of haloperidol-loaded nanocapsules and the free drug considering to its therapeutic action and side effects in rats. Firstly, it was prepared suspensions containing nanocapsules of haloperidol whose physicochemical characterization showed that haloperidol can be satisfactory encapsulated. After a first study using a pseudo-psychosis animal model, the haloperidol nanoencapsulated formulation demonstrated qualitative and quantitative therapeutic superiority, which were observed by the higher eficacy and action duration. In relation to extrapyramidal side effects, encapsulated formulation was able to prevent and/or minimize the characteristic acute and chronic movement disturbances, frequently observed with the free drug. In order to improve the results already obtained, a new formulation containing haloperidol nanocapsules was developed from the replacement of the oily core composed of caprylic and capric triglycerides in fish oil rich in polyunsaturated fatty acids, that has been described by its neuroprotective and antiapoptotic properties. This formulation showed physicalchemical suitability and reduced side effects in relation to the free drug, showing also ability to act in the prevention of oxidative stress which was observed by lower levels of lipid peroxidation, as well as an increase of antioxidant defenses in extrapyramidal regions. A third experimental phase was developed from the preparation of a new formulation of haloperidol containing grape seed oil in place of medium chain fatty acids mentioned above, which did not reach the necessary properties for a nanoformulation, but it was included for the comparative study of different nanocapsules formulations. The nanoformulation of haloperidol containing fish oil showed higher ability to prevent the motor side effects commonly seen with the free drug, which were observed by the maintenance of cell viability and control of free radical generation. Taken together, the results of this study point favorably to the development of nanocapsules formulations containing haloperidol, characterizing a positive perpective for minimizing of motor side effects consequent to the free drug. In this sense, these formulations can reduce the disabling physical limitations that cause embarrassment, contributing to a better quality of life of psychiatric patients.